SECTION IV  DRUGS WITH IMPORTANT ACTIONS ON
SMOOTH MUSCLE
Histamine, Serotonin,
& the Ergot Alkaloids
Bertram G. Katzung, MD, PhD
C ASE STUDY
A healthy 45-year-old physician attending a reunion in a
vacation hotel developed dizziness, redness of the skin over
the head and chest, and tachycardia while eating. A short
time later, another physician at the table developed similar
It has long been known that many tissues contain substances
that, when released by various stimuli, cause physiologic effects
such as reddening of the skin, pain or itching, and broncho-
spasm. Later, it was discovered that many of these substances
are also present in nervous tissue and have multiple functions.
Histamine and serotonin (5-hydroxytryptamine, 5-HT) are bio-
logically active amines that function as neurotransmitters and are
also found in non-neural tissues, have complex physiologic and
pathologic effects through multiple receptor subtypes, and are
often released locally. Together with endogenous peptides (see
Chapter 17), prostaglandins and leukotrienes (see Chapter 18),
and cytokines (see Chapter 55), they constitute the autacoid
group of drugs.
16
C H A P T E R
signs and symptoms with marked orthostatic hypotension.
The menu included a green salad, sautéed fish with rice, and
apple pie. What is the probable diagnosis? How would you
treat these patients?
Because of their broad and largely undesirable peripheral
effects, neither histamine nor serotonin has any clinical applica-
tion in the treatment of disease. However, compounds that
selectively activate certain receptor subtypes or selectively antago-
nize the actions of these amines are of considerable clinical value.
This chapter therefore emphasizes the basic pharmacology of the
agonist amines and the clinical pharmacology of the more selective
agonist and antagonist drugs. Obesity, a poorly understood condi-
tion, appears to involve many receptors, including some histamine
and serotonin receptors. It is discussed in a special section following
the discussion of serotonin and its antagonists. The ergot alkaloids,
compounds with partial agonist activity at serotonin and several
other receptors, are discussed at the end of the chapter.
277
278    SECTION IV  Drugs with Important Actions on Smooth Muscle
■■ HISTAMINE
Histamine was synthesized in 1907 and later isolated from
mammalian tissues. Early hypotheses concerning the possible
physiologic roles of tissue histamine were based on similarities
between the effects of intravenously administered histamine and
the symptoms of anaphylactic shock and tissue injury. Marked
species variation is observed, but in humans histamine is an
important mediator of immediate allergic (such as urticaria) and
inflammatory reactions, although it plays only a modest role in
anaphylaxis. Histamine plays an important role in gastric acid
secretion (see Chapter 62) and functions as a neurotransmitter
and neuromodulator (see Chapters 6 and 21). Newer evidence
indicates that histamine also plays a role in immune functions and
chemotaxis of white blood cells.
BASIC PHARMACOLOGY OF HISTAMINE
Chemistry & Pharmacokinetics
Histamine occurs in plants as well as in animal tissues and is a
component of some venoms and stinging secretions.
Histamine is formed by decarboxylation of the amino acid
l-histidine, a reaction catalyzed in mammalian tissues by the
enzyme histidine decarboxylase. Once formed, histamine is either
stored or rapidly inactivated. Very little histamine is excreted
unchanged. The major metabolic pathways involve conversion to
N-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic
acid (IAA). Certain neoplasms (systemic mastocytosis, urticaria pig-
mentosa, gastric carcinoid, and occasionally myelogenous leukemia)
are associated with increased numbers of mast cells or basophils and
with increased excretion of histamine and its metabolites.
CH2 CH2 NH2
HN N ment, C-reactive protein) and antibodies. Histamine has an
Histamine
Most tissue histamine is sequestered and bound in granules
(vesicles) in mast cells or basophils; the histamine content of
many tissues is directly related to their mast cell content. The
bound form of histamine is biologically inactive, but as noted
below, many stimuli can trigger the release of mast cell histamine,
allowing the free amine to exert its actions on surrounding tissues.
Mast cells are especially rich at sites of potential tissue injury—
nose, mouth, and feet; internal body surfaces; and blood vessels,
particularly at pressure points and bifurcations.
Non-mast cell histamine is found in several tissues, includ-
ing the brain, where it functions as a neurotransmitter. Strong
evidence implicates endogenous neurotransmitter histamine in
many brain functions such as neuroendocrine control, cardio­
vascular regulation, thermal and body weight regulation, and sleep
and arousal (see Chapter 21).
A second important nonneuronal site of histamine storage
and release is the enterochromaffin-like (ECL) cells of the fundus
of the stomach. ECL cells release histamine, one of the primary
gastric acid secretagogues, to activate the acid-producing parietal
cells of the mucosa (see Chapter 62).
Storage & Release of Histamine
The stores of histamine in mast cells can be released through
several mechanisms.
A. Immunologic Release
Immunologic processes account for the most important patho-
physiologic mechanism of mast cell and basophil histamine
release. These cells, if sensitized by IgE antibodies attached
to their surface membranes, degranulate explosively when
exposed to the appropriate antigen (see Figure 55–5, effector
phase). This type of release also requires energy and calcium.
Degranulation leads to the simultaneous release of histamine,
adenosine triphosphate (ATP), and other mediators that are
stored together in the granules. Histamine released by this
mechanism is a mediator in immediate (type I) allergic reac-
tions, such as hay fever and acute urticaria. Substances released
during IgG- or IgM-mediated immune reactions that activate
the complement cascade also release histamine from mast cells
and basophils.
By a negative feedback control mechanism mediated by H2
receptors, histamine appears to modulate its own release and that
of other mediators from sensitized mast cells in some tissues.
In humans, mast cells in skin and basophils show this negative
feedback mechanism; lung mast cells do not. Thus, histamine
may act to limit the intensity of the allergic reaction in the skin
and blood.
Endogenous histamine has a modulating role in a variety of
inflammatory and immune responses. Upon injury to a tissue,
released histamine causes local vasodilation and leakage of
plasma-containing mediators of acute inflammation (comple-
active chemotactic attraction for inflammatory cells (neutrophils,
eosinophils, basophils, monocytes, and lymphocytes). Histamine
inhibits the release of lysosome contents and several T- and
B-lymphocyte functions. Most of these actions are mediated by
H2 or H4 receptors. Release of peptides from nerves in response to
inflammation is also probably modulated by histamine acting on
presynaptic H3 receptors.
B. Chemical and Mechanical Release
Certain amines, including drugs such as morphine and tubocu-
rarine, can displace histamine from its bound form within cells.
This type of release does not require energy and is not associ-
ated with mast cell injury or explosive degranulation. Loss of
granules from the mast cell also releases histamine, because
sodium ions in the extracellular fluid rapidly displace the
amine from the complex. Chemical and mechanical mast cell
injury causes degranulation and histamine release. Compound
48/80, an experimental drug, selectively releases histamine
from tissue mast cells by an exocytotic degranulation process
requiring energy and calcium.

Pharmacodynamics
A. Mechanism of Action
Histamine exerts its biologic actions by combining with specific
receptors located on the cell membrane. Four different histamine
receptors have been characterized and are designated H1–H4; they
are described in Table 16–1. Unlike the other amine transmitter
receptors discussed previously, no subfamilies have been found
within these major types, although different splice variants of
several receptor types have been described.
All four receptor types have been cloned and belong to the
large superfamily of G protein-coupled receptors (GPCR). The
structures of the H1 and H2 receptors differ significantly and
appear to be more closely related to muscarinic and 5-HT1
receptors, respectively, than to each other. The H4 receptor has
about 40% homology with the H3 receptor but does not seem
to be closely related to any other histamine receptor. All four
histamine receptors have been shown to have constitutive activity
in some systems; thus, some antihistamines previously considered to
be traditional pharmacologic antagonists must now be considered
to be inverse agonists (see Chapters 1 and 2). Indeed, many first-
and second-generation H1 blockers function as inverse agonists.
Furthermore, a single molecule may be an agonist at one hista-
mine receptor and an antagonist or inverse agonist at another. For
example, clobenpropit, an agonist at H4 receptors, is an antagonist
or inverse agonist at H3 receptors (Table 16–1).
In the brain, H1 and H2 receptors are located on postsynaptic
membranes, whereas H3 receptors are predominantly presynaptic.
Activation of H1 receptors, which are present in endothelium,
smooth muscle cells, and nerve endings, usually elicits an increase
in phosphoinositol hydrolysis and an increase in inositol trispho-
sphate (IP3) and intracellular calcium. Activation of H2 receptors,
present in gastric mucosa, cardiac muscle cells, and some immune
cells, increases intracellular cyclic adenosine monophosphate
(cAMP) via Gs. Like the β2 adrenoceptor, under certain circum-
stances the H2 receptor may couple to Gq, activating the IP3-DAG
(inositol 1,4,5-trisphosphate-diacylglycerol) cascade. Activation
of H3 receptors decreases transmitter release from histaminergic
and other neurons, probably mediated by a decrease in calcium
influx through N-type calcium channels in nerve endings. H4
receptors are found mainly on leukocytes in the bone marrow
and circulating blood. H4 receptors appear to have very important
TABLE 16–1  Histamine receptor subtypes.
Receptor
Subtype Distribution
H1 Smooth muscle, endothelium, brain
H2 Gastric mucosa, cardiac muscle, mast cells, brain
H3 Presynaptic autoreceptors and heteroreceptors:
brain, myenteric plexus, other neurons
H4 Eosinophils, neutrophils, CD4 T cells
1
Inverse agonist.
cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; IP3, inositol trisphosphate.
CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    279
chemotactic effects on eosinophils and mast cells. In this role, they
seem to play a part in inflammation and allergy. They may also
modulate production of these cell types and they may mediate, in
part, the previously recognized effects of histamine on cytokine
production.
B. Tissue and Organ System Effects of Histamine
Histamine exerts powerful effects on smooth and cardiac muscle,
on certain endothelial and nerve cells, on the secretory cells of
the stomach, and on inflammatory cells. However, sensitivity to
histamine varies greatly among species. Guinea pigs are exquisitely
sensitive; humans, dogs, and cats somewhat less so; and mice and
rats very much less so.
1. Nervous system—Histamine is a powerful stimulant of
sensory nerve endings, especially those mediating pain and
itching. This H1-mediated effect is an important component of
the urticarial response and reactions to insect and nettle stings.
Some evidence suggests that local high concentrations can also
depolarize efferent (axonal) nerve endings (see Triple Response,
item 8 in this list). In the mouse, and probably in humans, respi-
ratory neurons signaling inspiration and expiration are modulated
by H1 receptors. H1 and H3 receptors play important roles in
appetite and satiety; antipsychotic drugs that block these receptors
cause significant weight gain (see Chapter 29). These receptors
may also participate in nociception. Presynaptic H3 receptors play
important roles in modulating release of several transmitters in
the nervous system. H3 agonists reduce the release of acetylcho-
line, amine, and peptide transmitters in various areas of the brain
and in peripheral nerves. An investigational inverse H3 agonist,
pitolisant (BF2649), appears to reduce drowsiness in patients
with narcolepsy.
2. Cardiovascular system—In humans, injection or infusion
of histamine causes a decrease in systolic and diastolic blood pres-
sure and an increase in heart rate. The blood pressure changes are
caused by the vasodilator action of histamine on arterioles and
precapillary sphincters; the increase in heart rate involves both
stimulatory actions of histamine on the heart and a reflex tachy-
cardia. Flushing, a sense of warmth, and headache may also occur
during histamine administration, consistent with the vasodila-
tion. Vasodilation elicited by small doses of histamine is caused
Postreceptor Partially Selective Partially Selective Antagonists or
Mechanism Agonists Inverse Agonists
1
Gq, ↑ IP3, DAG Histaprodifen Mepyramine, triprolidine, cetirizine
1 1
Gs, ↑ cAMP Amthamine Cimetidine, ranitidine, tiotidine
1
Gi, ↓ cAMP R-α-Methylhistamine, Thioperamide, iodophenpropit,
imetit, immepip clobenpropit,1 tiprolisant,1 proxyfan
1
Gi, ↓ cAMP Clobenpropit, imetit, Thioperamide
clozapine
280    SECTION IV  Drugs with Important Actions on Smooth Muscle
by H1-receptor activation and is mediated mainly by release of
nitric oxide from the endothelium (see Chapter 19). The decrease
in blood pressure is usually accompanied by a reflex tachycardia.
Higher doses of histamine activate the H2-mediated cAMP process
of vasodilation and direct cardiac stimulation. In humans, the
cardiovascular effects of small doses of histamine can usually be
antagonized by H1-receptor antagonists alone.
Histamine-induced edema results from the action of the
amine on H1 receptors in the vessels of the microcirculation,
especially the postcapillary vessels. The effect is associated
with the separation of the endothelial cells, which permits
the transudation of fluid and molecules as large as small
proteins into the perivascular tissue. This effect is responsible
for urticaria (hives), which signals the release of histamine in
the skin. Studies of endothelial cells suggest that actin and
myosin within these cells cause contraction, resulting in separa-
tion of the endothelial cells and increased permeability.
Direct cardiac effects of histamine include both increased
contractility and increased pacemaker rate. These effects are
mediated chiefly by H2 receptors. In human atrial muscle,
histamine can also decrease contractility; this effect is medi-
ated by H1 receptors. The physiologic significance of these
cardiac actions is not clear. Some of the cardiovascular signs
and symptoms of anaphylaxis are due to released histamine,
although several other mediators are involved and are much
more important than histamine in humans.
1. Bronchiolar smooth muscle—In both humans and guinea
pigs, histamine causes bronchoconstriction mediated by
H1 receptors. In the guinea pig, this effect is the cause of death
from histamine toxicity, but in humans with normal airways,
bronchoconstriction following small doses of histamine is not
marked. However, patients with asthma are very sensitive to
histamine. The bronchoconstriction induced in these patients
probably represents a hyperactive neural response, since such
patients also respond excessively to many other stimuli, and the
response to histamine can be blocked by autonomic block-
ing drugs such as ganglion blocking agents as well as by
H1-receptor antagonists (see Chapter 20). Although methacho-
line provocation is more commonly used, tests using small
doses of inhaled histamine have been used in the diagnosis of
bronchial hyperreactivity in patients with suspected asthma or
cystic fibrosis. Such individuals may be 100 to 1000 times
more sensitive to histamine (and methacholine) than are
normal subjects. Curiously, a few species (eg, rabbit) respond
to histamine with bronchodilation, reflecting the dominance of
the H2 receptor in their airways.
2. Gastrointestinal tract smooth muscle—Histamine causes
contraction of intestinal smooth muscle, and histamine-
induced contraction of guinea pig ileum is a standard bioassay
for this amine. The human gut is not as sensitive as that of the
guinea pig, but large doses of histamine may cause diarrhea,
partly as a result of this effect. This action of histamine is
mediated by H1 receptors.
3. Other smooth muscle organs—In humans, histamine generally
has insignificant effects on the smooth muscle of the eye and
genitourinary tract. However, pregnant women suffering
anaphylactic reactions may abort as a result of histamine-
induced contractions, and in some species the sensitivity of the
uterus is sufficient to form the basis for a bioassay.
4. Secretory tissue—Histamine has long been recognized as a
powerful stimulant of gastric acid secretion and, to a lesser
extent, of gastric pepsin and intrinsic factor production. The
effect is caused by activation of H2 receptors on gastric parietal
cells and is associated with increased adenylyl cyclase activity,
cAMP concentration, and intracellular Ca2+ concentration.
Other stimulants of gastric acid secretion such as acetylcholine
and gastrin do not increase cAMP even though their maximal
effects on acid output can be reduced—but not abolished—by
H2-receptor antagonists. These actions are discussed in more
detail in Chapter 62. Histamine also stimulates secretion in the
small and large intestine. In contrast, H3-selective histamine
agonists inhibit acid secretion stimulated by food or pentagas-
trin in several species.
Histamine has much smaller effects on the activity of
other glandular tissue at ordinary concentrations. Very high
concentrations can cause catecholamine release from the
adrenal medulla.
5. Metabolic effects—Recent studies of H3-receptor knockout
mice demonstrate that absence of this receptor results in
increased food intake, decreased energy expenditure, and
obesity. They also show insulin resistance and increased blood
levels of leptin and insulin. It is not yet known whether the
H3 receptor has a similar role in humans, but research is under
way to determine whether H3 agonists are useful in the
treatment of obesity.
6. The “triple response”—Intradermal injection of histamine
causes a characteristic red spot, edema, and flare response. The
effect involves three separate cell types: smooth muscle in the
microcirculation, capillary or venular endothelium, and
sensory nerve endings. At the site of injection, a reddening
appears owing to dilation of small vessels, followed soon by an
edematous wheal at the injection site and a red irregular flare
surrounding the wheal. The flare is said to be caused by an axon
reflex. A sensation of itching may accompany these effects.
Similar local effects may be produced by injecting histamine
liberators (compound 48/80, morphine, etc) intradermally or
by applying the appropriate antigens to the skin of a sensitized
person. Although most of these local effects can be prevented
by adequate doses of an H1-receptor-blocking agent, H2 and
H3 receptors may also be involved.
7. Other effects possibly mediated by histamine receptors—
In addition to the local stimulation of peripheral pain nerve
endings via H3 and H1 receptors, histamine may play a role
in nociception in the central nervous system. Burimamide, an
early candidate for H2-blocking action, and newer analogs with
no notable effect on H1, H2, or H3 receptors, have been shown
to have significant analgesic action in rodents when adminis-
tered into the central nervous system. The analgesia is said to be
comparable to that produced by opioids, but tolerance, respira-
tory depression, and constipation have not been reported.

Other Histamine Agonists
Small substitutions on the imidazole ring of histamine signifi-
cantly modify the selectivity of the compounds for the histamine
receptor subtypes. Some of these are listed in Table 16–1.
CLINICAL PHARMACOLOGY OF
HISTAMINE
Clinical Uses
In pulmonary function laboratories, histamine aerosol has rarely
been used as a provocative test of bronchial hyperreactivity.
Histamine has no other current clinical applications.
Toxicity & Contraindications
Adverse effects of histamine release, like those following admin-
istration of histamine, are dose related. Flushing, hypotension,
tachycardia, headache, urticaria, bronchoconstriction, and
gastrointestinal upset are noted. These effects are also observed after
the ingestion of spoiled fish (scombroid fish poisoning), and
histamine produced by bacterial action in the flesh of improperly
stored fish is the major causative agent.
Histamine should not be given to patients with asthma (except
as part of a carefully monitored test of pulmonary function) or to
patients with active ulcer disease or gastrointestinal bleeding.
HISTAMINE ANTAGONISTS
The effects of histamine released in the body can be reduced in
several ways. Physiologic antagonists, especially epinephrine,
have smooth muscle actions opposite to those of histamine, but
they act at different receptors. This is important clinically because
injection of epinephrine can be lifesaving in systemic anaphylaxis
and in other conditions in which massive release of histamine—
and other more important mediators—occurs.
Release inhibitors reduce the degranulation of mast cells that
results from immunologic triggering by antigen-IgE interaction.
Cromolyn and nedocromil appear to have this effect (see
Chapter 20) and have been used in the treatment of asthma.
Beta2-adrenoceptor agonists also appear capable of reducing
histamine release.
Histamine receptor antagonists represent a third approach to
the reduction of histamine-mediated responses. For over 70 years,
compounds have been available that competitively antagonize
many of the actions of histamine on smooth muscle. However,
not until the H2-receptor antagonist burimamide was described
in 1972 was it possible to antagonize the gastric acid-stimulating
activity of histamine. The development of selective H2-receptor
antagonists has led to more effective therapy for peptic disease (see
Chapter 62). Selective H3 and H4 antagonists are not yet available
for clinical use. However, potent and partially selective experimental
H 3-receptor antagonists, thioperamide and clobenpropit,
have been developed.
CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    281
■■ HISTAMINE RECEPTOR
ANTAGONISTS
H1-RECEPTOR ANTAGONISTS
Compounds that competitively block histamine or act as inverse
agonists at H1 receptors have been used in the treatment of allergic
conditions for many years, and in the discussion that follows are
referred to as antagonists. Many H1 antagonists are currently
marketed in the USA. A large number are available without
prescription, both alone and in combination formulations such as
“cold pills” and “sleep aids” (see Chapter 63).
BASIC PHARMACOLOGY OF
H1-RECEPTOR ANTAGONISTS
Chemistry & Pharmacokinetics
The H1 antagonists are conveniently divided into first-generation
and second-generation agents. These groups are distinguished by
the relatively strong sedative effects of most of the first-generation
drugs. The first-generation agents are also more likely to block
autonomic receptors. Second-generation H1 blockers are less
sedating, owing in part to reduced distribution into the central
nervous system. All the H1 antagonists are stable amines with
the general structure illustrated in Figure 16–1. Doses of some of
these drugs are given in Table 16–2.
These agents are rapidly absorbed after oral administration,
with peak blood concentrations occurring in 1–2 hours. They are
widely distributed throughout the body, and the first-generation
H1 blockers enter the central nervous system readily. Some of them
are extensively metabolized, primarily by microsomal systems in
the liver. Several of the second-generation agents are metabolized
by the CYP3A4 system and thus are subject to important interac-
tions when other drugs (such as ketoconazole) inhibit this subtype
of P450 enzymes. Most of the drugs have an effective duration
of action of 4–6 hours following a single dose, but meclizine and
several second-generation agents are longer-acting, with a dura-
tion of action of 12–24 hours. The newer agents are considerably
less lipid-soluble than the first-generation drugs and are substrates
of the P-glycoprotein transporter in the blood-brain barrier; as a
result, they enter the central nervous system with difficulty or not
at all. Many H1 antagonists have active metabolites. The active
metabolites of hydroxyzine, terfenadine, and loratadine are available
as drugs (cetirizine, fexofenadine, and desloratadine, respectively).
Pharmacodynamics
Both neutral H1 antagonists and inverse H1 agonists reduce or
block the actions of histamine by reversible competitive binding to
the H1 receptor. Several have been clearly shown to be inverse ago-
nists, and it is possible that all act by this mechanism. They have
negligible potency at the H2 receptor and little at the H3 receptor.
For example, histamine-induced contraction of bronchiolar or
gastrointestinal smooth muscle can be completely blocked by
282    SECTION IV  Drugs with Important Actions on Smooth Muscle
General structure Ethers or ethanolamine derivative
X Y C C N
X is: C or N
Y is: C, O, or omitted Diphenhydramine or dimenhydrinate
Alkylamine derivative
CI CH3
CH CH2 CH2 N C
CH3
N
Chlorpheniramine
FIGURE 16–1  General structure of H1-antagonist drugs and examples of the major subgroups. Subgroup names are based on the shaded
moieties.
these agents, but histamine-stimulated gastric acid secretion and
the stimulation of the heart are unaffected.
The first-generation H1-receptor antagonists have many actions
in addition to blockade of the actions of histamine. The large
number of these actions probably results from the similarity of the
general structure (Figure 16–1) to the structure of drugs that have
effects at muscarinic cholinoceptor, α adrenoceptor, serotonin,
and local anesthetic receptor sites. Some of these actions are of
therapeutic value and some are undesirable.
1. Sedation—A common effect of first-generation H1 antagonists
is sedation, but the intensity of this effect varies among chemical
subgroups (Table 16–2) and among patients as well. The effect is
sufficiently prominent with some agents to make them useful as
“sleep aids” (see Chapter 63) and unsuitable for daytime use. The
effect resembles that of some antimuscarinic drugs and is considered
very different from the disinhibited sedation produced by sedative-
hypnotic drugs. Compulsive use has not been reported. At ordinary
dosages, children occasionally (and adults rarely) manifest excitation
rather than sedation. At very high toxic dose levels, marked stimu-
lation, agitation, and even seizures may precede coma. Second-
generation H1 antagonists have little or no sedative or stimulant
actions. These drugs (or their active metabolites) also have far fewer
autonomic effects than the first-generation antihistamines.
2. Antinausea and antiemetic actions—Several first-generation
H1 antagonists have significant activity in preventing motion sick-
ness (Table 16–2). They are less effective against an episode of
motion sickness already present. Certain H1 antagonists, notably
CH3
CH O CH2 CH2 N
CH3
Piperidine derivative
OH
N OH CH3
CH2 CH2 CH2 CH C COOH
CH3
Fexofenadine
doxylamine (in Bendectin), were used widely in the past in the
treatment of nausea and vomiting of pregnancy (see below). Although
Bendectin was withdrawn in 1983, a similar formulation, combining
doxylamine and pyridoxine (Diclegis), was approved by the US Food
and Drug Administration (FDA) in 2013.
3. Antiparkinsonism effects—Some of the H1 antagonists,
especially diphenhydramine, have significant acute suppressant
effects on the extrapyramidal symptoms associated with certain
antipsychotic drugs. This drug is given parenterally for acute
dystonic reactions to antipsychotics.
4. Antimuscarinic actions—Many first-generation agents,
especially those of the ethanolamine and ethylenediamine sub-
groups, have significant atropine-like effects on peripheral mus-
carinic receptors. This action may be responsible for some of the
(uncertain) benefits reported for nonallergic rhinorrhea but may
also cause urinary retention and blurred vision.
5. Adrenoceptor-blocking actions—Alpha-receptor-blocking
effects can be demonstrated for many H1 antagonists, especially
those in the phenothiazine subgroup, eg, promethazine. This
action may cause orthostatic hypotension in susceptible indi-
viduals. Beta-receptor blockade is not significant.
6. Serotonin-blocking actions—Strong blocking effects at
serotonin receptors have been demonstrated for some first-
generation H1 antagonists, notably cyproheptadine. This drug
is promoted as an antiserotonin agent and is discussed with that
 CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    283

TABLE 16–2  Some H1 antihistaminic drugs in clinical use.

Drugs Usual Adult Dose Anticholinergic Activity Comments

FIRST-GENERATION ANTIHISTAMINES
Ethanolamines
Carbinoxamine (Clistin) 4–8 mg +++ Slight to moderate sedation
Dimenhydrinate (salt of 50 mg +++ Marked sedation; anti-motion sickness activity
diphenhydramine) (Dramamine)
Diphenhydramine (Benadryl, etc) 25–50 mg +++ Marked sedation; anti-motion sickness activity
Piperazine derivatives
Hydroxyzine (Atarax, etc) 15–100 mg nd Marked sedation
Cyclizine (Marezine) 25–50 mg — Slight sedation; anti-motion sickness activity
Meclizine (Bonine, etc) 25–50 mg — Slight sedation; anti-motion sickness activity
Alkylamines
Brompheniramine (Dimetane, etc) 4–8 mg + Slight sedation
Chlorpheniramine (Chlor-Trimeton, 4–8 mg + Slight sedation; common component of OTC “cold”
etc) medication
Phenothiazine derivative
Promethazine (Phenergan, etc) 10–25 mg +++ Marked sedation; antiemetic; a-block
Miscellaneous
Cyproheptadine (Periactin, etc) 4 mg + Moderate sedation; significant antiserotonin activity;
mixed evidence for use as an appetite stimulant
SECOND-GENERATION ANTIHISTAMINES
Piperidine
Fexofenadine (Allegra, etc) 60 mg —
Miscellaneous
Loratadine (Claritin, etc), 10 mg (desloratadine, — Longer action; used at 5 mg dosage
desloratadine (Clarinex) 5 mg)
Cetirizine (Zyrtec, etc) 5–10 mg —
nd, no data found.

drug group. Nevertheless, its structure resembles that of the pheno-
thiazine antihistamines, and it is a potent H1-blocking agent.
7. Local anesthesia—Several first-generation H1 antagonists
are potent local anesthetics. They block sodium channels in excit-
able membranes in the same fashion as procaine and lidocaine.
Diphenhydramine and promethazine are actually more potent
than procaine as local anesthetics. They are occasionally used to
produce local anesthesia in patients allergic to conventional local
anesthetic drugs. A small number of these agents also block potas-
sium channels; this action is discussed below (see Toxicity).
CLINICAL PHARMACOLOGY OF
H1-RECEPTOR ANTAGONISTS
Clinical Uses
First-generation H1-receptor blockers are still commonly used
over-the-counter drugs. The prevalence of allergic conditions
and the relative safety of the drugs contribute to this heavy use.
However, the fact that they do cause sedation contributes to heavy
prescribing as well as over-the-counter use of second-generation
antihistamines.

8. Other actions—Certain H1 antagonists, eg, cetirizine, inhibit

mast cell release of histamine and some other mediators of inflam-
mation. This action is not due to H1-receptor blockade and may
reflect an H4-receptor effect (see below). The mechanism is not
fully understood but could play a role in the beneficial effects of
these drugs in the treatment of allergies such as rhinitis. A few
H1 antagonists (eg, terfenadine, acrivastine) have been shown to
inhibit the P-glycoprotein transporter found in cancer cells, the
epithelium of the gut, and the capillaries of the brain. The signifi-
cance of this effect is not known.
A. Allergic Reactions
The H1 antihistaminic agents are often the first drugs used to
prevent or treat the symptoms of allergic reactions. In allergic
rhinitis (hay fever), the H1 antagonists are second-line drugs
after glucocorticoids administered by nasal spray. In urticaria, in
which histamine is the primary mediator, the H1 antagonists are
the drugs of choice and are often quite effective if given before
exposure. However, in bronchial asthma, which involves several
mediators, the H1 antagonists are largely ineffective.
284    SECTION IV  Drugs with Important Actions on Smooth Muscle
Angioedema may be precipitated by histamine release but
appears to be maintained by peptide kinins that are not affected by
antihistaminic agents. For atopic dermatitis, antihistaminic drugs
such as diphenhydramine are used mostly for their sedative side
effect, which reduces awareness of itching.
The H1 antihistamines used for treating allergic conditions
such as hay fever are usually selected with the goal of minimiz-
ing sedative effects; in the USA, the drugs in widest use are
the alkylamines and the second-generation nonsedating agents.
However, the sedative effect and the therapeutic efficacy of differ-
ent agents vary widely among individuals. In addition, the clinical
effectiveness of one group may diminish with continued use, and
switching to another group may restore drug effectiveness for as
yet unexplained reasons.
The second-generation H1 antagonists are used mainly for
the treatment of allergic rhinitis and chronic urticaria. Several
double-blind comparisons with older agents (eg, chlorpheniramine)
indicated about equal therapeutic efficacy. However, sedation
and interference with safe operation of machinery, which occur
in about 50% of subjects taking first-generation antihistamines,
occurred in only about 7% of subjects taking second-generation
agents. The newer drugs are much more expensive, even in over-
the-counter generic formulations.
B. Motion Sickness and Vestibular Disturbances
Scopolamine (see Chapter 8) and certain first-generation
H1 antagonists are the most effective agents available for the
prevention of motion sickness. The antihistaminic drugs with the
greatest effectiveness in this application are diphenhydramine and
promethazine. Dimenhydrinate, which is promoted almost exclu-
sively for the treatment of motion sickness, is a salt of diphen-
hydramine and has similar efficacy. The piperazines (cyclizine
and meclizine) also have significant activity in preventing motion
sickness and are less sedating than diphenhydramine in most
patients. Dosage is the same as that recommended for allergic
disorders (Table 16–2). Both scopolamine and the H1 antagonists
are more effective in preventing motion sickness when combined
with ephedrine or amphetamine.
It has been claimed that the antihistaminic agents effective
in prophylaxis of motion sickness are also useful in Méniére’s
syndrome, but efficacy in the latter condition is not established.
C. Nausea and Vomiting of Pregnancy
Several H1-antagonist drugs have been studied for possible use
in treating “morning sickness.” The piperazine derivatives were
withdrawn from such use when it was demonstrated that they
have teratogenic effects in rodents. Doxylamine, an ethanolamine
H1 antagonist, was promoted for this application as a component of
Bendectin, a prescription medication that also contained pyridox-
ine. Possible teratogenic effects of doxylamine were widely publi-
cized in the lay press after 1978 as a result of a few case reports
of fetal malformation that occurred after maternal ingestion of
Bendectin. However, several large prospective studies disclosed no
increase in the incidence of birth defects, thereby justifying the
reintroduction of a similar product.
Toxicity
The wide spectrum of nonantihistaminic effects of the
H1 antihistamines is described above. Several of these effects
(sedation, antimuscarinic action) have been used for thera-
peutic purposes, especially in over-the-counter remedies (see
Chapter 63). Nevertheless, these two effects constitute the
most common undesirable actions when these drugs are used
to block peripheral histamine receptors.
Less common toxic effects of systemic use include excitation
and convulsions in children, postural hypotension, and allergic
responses. Drug allergy is relatively common after topical use
of H1 antagonists. The effects of severe systemic overdosage of
the older agents resemble those of atropine overdosage and are
treated in the same way (see Chapters 8 and 58). Overdosage of
astemizole or terfenadine may induce cardiac arrhythmias; the
same effect may be caused at normal dosage by interaction with
enzyme inhibitors (see Drug Interactions). These drugs are no
longer marketed in the USA.
Drug Interactions
Lethal ventricular arrhythmias occurred in several patients taking
either of the early second-generation agents, terfenadine or
astemizole, in combination with ketoconazole, itraconazole, or
macrolide antibiotics such as erythromycin. These antimicrobial
drugs inhibit the metabolism of many drugs by CYP3A4 and
cause significant increases in blood concentrations of the anti-
histamines. The mechanism of this toxicity involves blockade of
the HERG (IKr) potassium channels in the heart that contribute
to repolarization of the action potential (see Chapter 14). The
result is prolongation and a change in shape of the action poten-
tial, and these changes lead to arrhythmias. Both terfenadine and
astemizole were withdrawn from the US market in recognition of
these problems. Where still available, terfenadine and astemizole
should be considered to be contraindicated in patients taking
ketoconazole, itraconazole, or macrolides and in patients with
liver disease. Grapefruit juice also inhibits CYP3A4 and has been
shown to increase blood levels of terfenadine significantly.
For those H1 antagonists that cause significant sedation,
concurrent use of other drugs that cause central nervous system
depression produces additive effects and is contraindicated while
driving or operating machinery. Similarly, the autonomic blocking
effects of older antihistamines are additive with those of antimus-
carinic and α-blocking drugs.
H2-RECEPTOR ANTAGONISTS
The development of H2-receptor antagonists was based on the
observation that H1 antagonists had no effect on histamine-
induced acid secretion in the stomach. Molecular manipulation of
the histamine molecule resulted in drugs that blocked acid secre-
tion and had no H1 agonist or antagonist effects. Like the other
histamine receptors, the H2 receptor displays constitutive activity,
and some H2 blockers are inverse agonists.
The high prevalence of peptic ulcer disease created great interest
in the therapeutic potential of the H2-receptor antagonists when

first discovered. Although these agents are not the most efficacious
available, their ability to reduce gastric acid secretion with very low
toxicity has made them extremely popular as over-the-counter prep-
arations. These drugs are discussed in more detail in Chapter 62.
H3- & H4-RECEPTOR ANTAGONISTS
Although no selective H3 or H4 ligands are presently available
for general clinical use, there is great interest in their therapeutic
potential. H3-selective ligands may be of value in sleep disorders,
narcolepsy, obesity, and cognitive and psychiatric disorders.
Tiprolisant, an inverse H3-receptor agonist, has been shown to
reduce sleep cycles in mutant mice and in humans with narco-
lepsy. Increased obesity has been demonstrated in both H1- and
H3-receptor knockout mice; however, H3 inverse agonists decrease
feeding in obese mouse models. As noted in Chapter 29, several
atypical antipsychotic drugs have significant affinity for H3 receptors
(and cause weight gain).
Because of the homology between the H3 and H4 receptors,
some H3 ligands also have affinity for the H4 receptor. H4 blockers
have potential in chronic inflammatory conditions such as
asthma, in which eosinophils and mast cells play a prominent role.
No selective H4 ligand is available for use in humans, but in addi-
tion to research agents listed in Table 16–1, many H1-selective
blockers (eg, diphenhydramine, cetirizine, loratadine) show some
affinity for this receptor. Several studies have suggested that
H4-receptor antagonists may be useful in pruritus, asthma, allergic
rhinitis, and pain conditions.
■■ SEROTONIN
(5-HYDROXYTRYPTAMINE)
Before the identification of 5-hydroxytryptamine (5-HT), it was
known that when blood is allowed to clot, a vasoconstrictor (tonic)
substance is released from the clot into the serum. This substance
was called serotonin. Independent studies established the existence
of a smooth muscle stimulant in intestinal mucosa. This was
called enteramine. The synthesis of 5-hydroxytryptamine in 1951
led to the identification of serotonin and enteramine as the same
metabolite of 5-hydroxytryptophan.
Serotonin is an important neurotransmitter, a local hormone
in the gut, a component of the platelet clotting process, and is
thought to play a role in migraine headache and several other clini-
cal conditions, including carcinoid syndrome. This syndrome is an
unusual manifestation of carcinoid tumor, a neoplasm of entero-
chromaffin cells. In patients whose tumor is not surgically resect-
able, a serotonin antagonist may constitute a useful treatment.
BASIC PHARMACOLOGY OF SEROTONIN
Chemistry & Pharmacokinetics
Like histamine, serotonin is widely distributed in nature, being
found in plant and animal tissues, venoms, and stings. It is syn-
thesized in biologic systems from the amino acid l-tryptophan
CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    285
CH2 NH3+
CH
COO–
N
H
L-tryptophan
HO CH2 NH2
CH2
N
H
5-Hydroxytryptamine (serotonin)
H
O CH2 N CH3
CH2 C
H3C
O
N
H
Melatonin
(N-acetyl-5-methoxytryptamine)
FIGURE 16–2  Synthesis of serotonin and melatonin from
l-tryptophan.
by hydroxylation of the indole ring followed by decarboxylation
of the amino acid (Figure 16–2). Hydroxylation at C5 by
tryptophan hydroxylase-1 is the rate-limiting step and can be
blocked by p-chlorophenylalanine (PCPA; fenclonine) and by
p-chloroamphetamine. These agents have been used experimen-
tally to reduce serotonin synthesis in carcinoid syndrome but are
too toxic for general clinical use. Telotristat ethyl, an orally active
hydroxylase inhibitor, has been approved for the treatment of
diarrhea due to carcinoid tumor.
After synthesis, the free amine is stored in vesicles or is rapidly
inactivated, usually by oxidation by monoamine oxidase (MAO).
In the pineal gland, serotonin serves as a precursor of melatonin, a
melanocyte-stimulating hormone that has complex effects in several
tissues. In mammals (including humans), over 90% of the serotonin
in the body is found in enterochromaffin cells in the gastrointestinal
tract. In the blood, serotonin is found in platelets, which are able to
concentrate the amine by means of an active serotonin transporter
mechanism (SERT) similar to that in the membrane of serotonergic
nerve endings. Once transported into the platelet or nerve ending,
5-HT is concentrated in vesicles by a vesicle-associated transporter
(VAT) that is blocked by reserpine. Serotonin is also found in the
raphe nuclei of the brainstem, which contain cell bodies of sero-
tonergic neurons that synthesize, store, and release serotonin as a
transmitter. Stored serotonin can be depleted by reserpine in much
the same manner as this drug depletes catecholamines from vesicles
in adrenergic nerves and the adrenal medulla (see Chapter 6).
286    SECTION IV  Drugs with Important Actions on Smooth Muscle

Brain serotonergic neurons are involved in numerous diffuse Pharmacodynamics

functions such as mood, sleep, appetite, and temperature regula-
tion, as well as the perception of pain, the regulation of blood
pressure, and vomiting (see Chapter 21). Serotonin is clearly
involved in psychiatric depression (see Chapter 30) and also
appears to be involved in conditions such as anxiety and migraine.
Serotonergic neurons are found in the enteric nervous system of
the gastrointestinal tract and around blood vessels. In rodents (but
not in humans), serotonin is also found in mast cells.
The function of serotonin in enterochromaffin cells is not fully
understood. These cells synthesize serotonin, store the amine in a
complex with adenosine triphosphate (ATP) and other substances
in granules, and release serotonin in response to mechanical and
neuronal stimuli. This serotonin interacts in a paracrine fashion
with several different 5-HT receptors in the gut (see Chapter 62).
Some of the released serotonin diffuses into blood vessels and is
taken up and stored in platelets.
Serotonin is metabolized by MAO, and the intermediate
product, 5-hydroxyindoleacetaldehyde, is further oxidized by
aldehyde dehydrogenase to 5-hydroxyindoleacetic acid (5-HIAA).
In humans consuming a normal diet, the excretion of 5-HIAA is
a measure of serotonin synthesis. Therefore, the 24-hour excre-
tion of 5-HIAA can be used as a diagnostic test for tumors that
synthesize excessive quantities of serotonin, especially carcinoid
tumor. A few foods (eg, bananas) contain large amounts of
serotonin or its precursors and must be prohibited during such
diagnostic tests.
A. Mechanisms of Action
Serotonin exerts many actions and, like histamine, displays
many species differences, making generalizations difficult. The
actions of serotonin are mediated through a remarkably large
number of cell membrane receptors. The serotonin receptors
that have been characterized thus far are listed in Table 16–3.
Seven families of 5-HT-receptor subtypes (those given numeric
subscripts 1 through 7) have been identified, six involving G
protein-coupled receptors of the usual seven-transmembrane
serpentine type and one a ligand-gated ion channel. The latter
(5-HT3) receptor is a member of the nicotinic family of Na+/K+
channel proteins.
B. Tissue and Organ System Effects
1. Nervous system—Serotonin is present in a variety of sites
in the brain. Its role as a neurotransmitter and its relation to the
actions of drugs acting in the central nervous system are discussed
in Chapters 21 and 30. Serotonin is also a precursor of melatonin in
the pineal gland (Figure 16–2; see Box: Melatonin Pharmacology).
Repinotan, a 5-HT1A agonist currently in clinical trials, appears to
have some antinociceptive action at higher doses while reversing
opioid-induced respiratory depression.
5-HT3 receptors in the gastrointestinal tract and in the vomit-
ing center of the medulla participate in the vomiting reflex (see
Chapter 62). They are particularly important in vomiting caused

TABLE 16–3  Serotonin receptor subtypes currently recognized. (See also Chapter 21.)
Receptor Postreceptor Partially Selective
Subtype Distribution Mechanism Partially Selective Agonists Antagonists
1
5-HT1A Raphe nuclei, hippocampus Gi, ↓ cAMP 8-OH-DPAT, repinotan WAY1006351
1
5-HT1B Substantia nigra, globus Gi, ↓ cAMP Sumatriptan, L694247
pallidus, basal ganglia
5-HT1D Brain Gi, ↓ cAMP Sumatriptan, eletriptan
5-HT1E Cortex, putamen Gi, ↓ cAMP
1
5-HT1F Cortex, hippocampus Gi, ↓ cAMP LY3344864
5-HT1P Enteric nervous system Go, slow EPSP 5-Hydroxyindalpine Renzapride
5-HT2A Platelets, smooth muscle, Gq, ↑ IP3 α-Methyl-5-HT, DOI1 Ketanserin
cerebral cortex
5-HT2B Stomach fundus Gq, ↑ IP3 α-Methyl-5-HT, DOI1 RS1274451
5-HT2C Choroid, hippocampus, Gq, ↑ IP3 α-Methyl-5-HT, DOI,1 lorcaserin Mesulergine
substantia nigra
5-HT3 Area postrema, sensory and Receptor is an Na+/ 2-Methyl-5-HT, m-chlorophenylbiguanide Granisetron,
enteric nerves K+ ion channel ondansetron,
others
1
5-HT4 CNS and myenteric neurons, Gs, ↑ cAMP BIMU8, renzapride, metoclopramide GR1138081
smooth muscle
5-HT5A,B Brain ↓ cAMP
5-HT6,7 Brain Gs, ↑ cAMP Clozapine (5-HT7)
1
Research agents; for chemical names see Alexander SPH, Mathie A, Peters JA: Guide to receptors and channels (GRAC). Br J Pharmacol 2011;164 (Suppl 1):S16–17, 116–117.
cAMP, cyclic adenosine monophosphate; EPSP, excitatory postsynaptic potential; IP3, inositol trisphosphate.

Melatonin Pharmacology
Melatonin is N-acetyl-5-methoxytryptamine (Figure 16–2), a
simple methoxylated and N-acetylated product of serotonin
found in the pineal gland. It is produced and released primarily
at night and has long been suspected of playing a role in diurnal
cycles of animals and the sleep-wake behavior of humans.
Melatonin receptors have been characterized in the central
nervous system and several peripheral tissues. In the brain, MT1
and MT2 receptors are found in membranes of neurons in the supra-
chiasmatic nucleus of the hypothalamus, an area associated—
from lesioning experiments—with circadian rhythm. MT1 and
MT2 are seven-transmembrane Gi protein-coupled receptors.
The result of receptor binding is inhibition of adenylyl cyclase. A
third receptor, MT3, is an enzyme; binding to this site has a poorly
defined physiologic role, possibly related to intraocular pressure.
Activation of the MT1 receptor results in sleepiness, whereas the
MT2 receptor may be related to the light-dark synchronization of
the biologic circadian clock. Melatonin has also been implicated
in energy metabolism and obesity, and administration of the
agent reduces body weight in certain animal models. However,
its role in these processes is poorly understood, and there is no
evidence that melatonin itself is of any value in obesity in humans.
by chemical triggers such as cancer chemotherapy drugs. 5-HT1P
and 5-HT4 receptors also play important roles in enteric nervous
system function.
Like histamine, serotonin is a potent stimulant of pain and itch
sensory nerve endings and is responsible for some of the symp-
toms caused by insect and plant stings. In addition, serotonin is a
powerful activator of chemosensitive endings located in the coro-
nary vascular bed. Activation of 5-HT3 receptors on these afferent
vagal nerve endings is associated with the chemoreceptor reflex
(also known as the Bezold-Jarisch reflex). The reflex response con-
sists of marked bradycardia and hypotension, and its physiologic
role is uncertain. The bradycardia is mediated by vagal outflow
to the heart and can be blocked by atropine. The hypotension is
a consequence of the decrease in cardiac output that results from
bradycardia. A variety of other agents can activate the chemore-
ceptor reflex. These include nicotinic cholinoceptor agonists and
some cardiac glycosides, eg, ouabain.
Although serotonergic neurons are not found below the
site of injury to the adult spinal cord, constitutive activity
of 5-HT receptors may play a role following such a lesion—
administration of 5-HT2 blockers appears to reduce skeletal
muscle spasm following this type of injury.
2. Respiratory system—Serotonin has a small direct stimulant
effect on bronchiolar smooth muscle in normal humans, probably
via 5-HT2A receptors. It also appears to facilitate acetylcholine
release from bronchial vagal nerve endings. In patients with
carcinoid syndrome, episodes of bronchoconstriction occur in
response to elevated levels of the amine or peptides released from
CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    287
Other studies suggest that melatonin has antiapoptotic effects
in experimental models. Recent research implicates melatonin
receptors in depressive disorders. Insomnia associated with
autism spectrum disorder may respond to melatonin.
Melatonin is promoted commercially as a sleep aid by
the food supplement industry (see Chapter 64). There is an
extensive literature supporting its use in ameliorating jet lag.
It is used in oral doses of 0.5–5 mg, usually administered at the
destination bedtime. Ramelteon is a selective MT1 and MT2
agonist that is approved for the medical treatment of insom-
nia. This drug has no addiction liability (it is not a controlled
substance), and it appears to be distinctly more efficacious
than melatonin (but less efficacious than benzodiazepines) as
a hypnotic. It is metabolized by P450 enzymes and should not
be used in individuals taking CYP1A2 inhibitors. It has a half-life
of 1–3 hours and an active metabolite with a half-life of up to
5 hours. Ramelteon may increase prolactin levels. Tasimelteon
is a newer MT1 and MT2 agonist that is approved for non-
24-hour sleep-wake disorder. Agomelatine, an MT1 and MT2
agonist and a 5-HT2C antagonist, is approved in Europe for use
in major depressive disorder.
the tumor. Serotonin may also cause hyperventilation as a result
of the chemoreceptor reflex or stimulation of bronchial sensory
nerve endings.
3. Cardiovascular system—Serotonin directly causes the
contraction of vascular smooth muscle, mainly through 5-HT2
receptors. In humans, serotonin is a powerful vasoconstrictor except
in skeletal muscle and the heart, where it dilates blood vessels.
At least part of the 5-HT-induced vasodilation requires the
presence of vascular endothelial cells. When the endothelium
is damaged, coronary vessels are constricted by 5-HT. As noted
previously, serotonin can also elicit reflex bradycardia by activa-
tion of 5-HT3 receptors on chemoreceptor nerve endings. A
triphasic blood pressure response is often seen following injec-
tion of serotonin in experimental animals. Initially, there is a
decrease in heart rate, cardiac output, and blood pressure caused
by the chemoreceptor response. After this decrease, blood pressure
increases as a result of vasoconstriction. The third phase is again
a decrease in blood pressure attributed to vasodilation in vessels
supplying skeletal muscle. In contrast, pulmonary and renal vessels
seem very sensitive to the vasoconstrictor action of serotonin.
Studies in knockout mice suggest that 5-HT, acting on
5-HT1A, 5-HT2, and 5-HT4 receptors, is needed for normal
cardiac development in the fetus. On the other hand, chronic
exposure of adults to 5-HT2B agonists is associated with val-
vulopathy and adult mice lacking the 5-HT2B receptor gene are
protected from cardiac hypertrophy. Preliminary studies suggest
that 5-HT2B antagonists can prevent development of pulmonary
hypertension in animal models.
288    SECTION IV  Drugs with Important Actions on Smooth Muscle
Serotonin Syndrome and Similar Syndromes
Excess synaptic serotonin causes a serious, potentially fatal syn-
drome that is diagnosed on the basis of a history of administration
of a serotonergic drug within recent weeks and physical findings.
It has some characteristics in common with neuroleptic malignant
syndrome (NMS) and malignant hyperthermia (MH), but its patho-
physiology and management are quite different (Table 16–4).
As suggested by the drugs that precipitate it, serotonin
syndrome occurs when overdose with a single drug, or concur-
rent use of several drugs, results in excess serotonergic activity in
the central nervous system. It is predictable and not idiosyncratic,
but milder forms may easily be misdiagnosed. In experimental
Serotonin also constricts veins, and venoconstriction with
increased capillary filling appears to be responsible for the flush
that is observed after serotonin administration or release from a
carcinoid tumor. Serotonin has small direct positive chronotropic
and inotropic effects on the heart, which are probably of no clini-
cal significance. However, prolonged elevation of the blood level
of serotonin (which occurs in carcinoid syndrome) is associated
with pathologic alterations in the endocardium (subendocardial
fibroplasia), which may result in valvular or electrical malfunction.
Serotonin causes blood platelets to aggregate by activating 5-HT2
receptors. This response, in contrast to aggregation induced during
normal clot formation, is not accompanied by the release of serotonin
stored in the platelets. The physiologic role of this effect is unclear.
4. Gastrointestinal tract—Serotonin is a powerful stimulant
of gastrointestinal smooth muscle, increasing tone and facili-
tating peristalsis. This action is caused by the direct action of
serotonin on 5-HT2 smooth muscle receptors plus a stimulating
action on ganglion cells located in the enteric nervous system (see
Chapter 6). 5-HT1A and 5-HT7 receptors may also be involved.
Activation of 5-HT4 receptors in the enteric nervous system causes
increased acetylcholine release and thereby mediates a motility-
enhancing or “prokinetic” effect of selective serotonin agonists
such as cisapride. These agents are useful in several gastrointestinal
disorders (see Chapter 62). Overproduction of serotonin (and other
substances) in carcinoid tumor is associated with severe diarrhea.
TABLE 16–4  Characteristics of serotonin syndrome and other hyperthermic syndromes.
Syndrome Precipitating Drugs
Serotonin SSRIs, second-generation antidepressants,
syndrome MAOIs, linezolid, tramadol, meperidine,
fentanyl, ondansetron, sumatriptan,
MDMA, LSD, St. John’s wort, ginseng
Neuroleptic D2-blocking antipsychotics
malignant
syndrome
Malignant Volatile anesthetics, succinylcholine
hyperthermia
1
Precipitating drugs should be discontinued immediately. First-line therapy is in boldface font.
LSD, lysergic acid diethylamide, MAOIs, monoamine oxidase inhibitors; MDMA, methylenedioxy-methamphetamine (ecstasy); SSRIs, selective serotonin reuptake inhibitors.
animal models, many of the signs of the syndrome can be
reversed by administration of 5-HT2 antagonists; however, other
5-HT receptors may be involved as well. Dantrolene is of no value,
unlike the treatment of MH.
NMS is idiosyncratic rather than predictable and appears to
be associated with hypersensitivity to the parkinsonism-inducing
effects of D2-blocking antipsychotics in certain individuals. MH is
associated with a genetic defect in the RyR1 calcium channel of
skeletal muscle sarcoplasmic reticulum that permits uncontrolled
calcium release from the sarcoplasmic reticulum when precipitat-
ing drugs are given (see Chapter 27).
Serotonin has little effect on gastrointestinal secretions, and what
effects it has are generally inhibitory.
5. Skeletal muscle and the eye—5-HT2 receptors are pres-
ent on skeletal muscle membranes, but their physiologic role is
not understood. As discussed in the box, serotonin syndrome
is associated with skeletal muscle contractions and precipi-
tated when MAO inhibitors are given with serotonin agonists,
especially antidepressants of the selective serotonin reuptake
inhibitor class (SSRIs; see Chapter 30). Although the hyper-
thermia of serotonin syndrome results from excessive muscle
contraction, serotonin syndrome is probably caused by a
central nervous system effect of these drugs (Table 16–4 and Box:
Serotonin Syndrome and Similar Syndromes).
Studies in animal models of glaucoma indicate that 5-HT2A
agonists reduce intraocular pressure. This action can be blocked
by ketanserin and similar 5-HT2 antagonists.
CLINICAL PHARMACOLOGY OF
SEROTONIN
Serotonin Agonists
Serotonin has no clinical applications as a drug. However,
several receptor subtype-selective agonists have proved to be of
value. Buspirone, a 5-HT1A agonist, has received attention as an
Clinical Presentation Therapy1
Hypertension, hyperreflexia, tremor, Sedation (benzodiazepines),
clonus, hyperthermia, hyperactive bowel paralysis, intubation, and ventilation;
sounds, diarrhea, mydriasis, agitation, consider 5-HT2 block with cyproheptadine
coma; onset within hours or chlorpromazine
Acute severe parkinsonism; hypertension, Diphenhydramine (parenteral),
hyperthermia, normal or reduced bowel cooling if temperature is very high,
sounds; onset over 1–3 days sedation with benzodiazepines
Hyperthermia, muscle rigidity, hyperten- Dantrolene, cooling
sion, tachycardia; onset within minutes

Treatment of Obesity
It is said that much of the world is experiencing an “epidemic
of obesity.” This statement is based on statistics showing that in
the USA and many other countries, 30–40% of the population
is above optimal weight, and that the excess weight (especially
abdominal fat) is often associated with the metabolic syndrome
and increased risks of cardiovascular disease and diabetes. Since
eating behavior is an expression of endocrine, neurophysiologic,
and psychological processes, prevention and treatment of obe-
sity are challenging. There is considerable scientific and financial
interest in developing pharmacologic therapy for the condition.
Although obesity can be defined as excess adipose tissue,
it is currently quantitated by means of the body mass index
(BMI), calculated from BMI = weight (in kilograms)/height2 (in
meters). Using this measure, the range of normal BMI is defined
as 18.5–24.9; overweight, 25–29.9; obese, 30–39.9; and morbidly
obese (ie, at very high risk), ≥40. (Underweight persons, ie, those
with a BMI < 18, also have an increased [but smaller] risk of health
problems.) Some extremely muscular individuals may have a BMI
higher than 25 and no excess fat; however, the BMI scale gener-
ally correlates with the degree of obesity and with risk. A second
metric, which may be an even better predictor of cardiovascular
risk, is the ratio of waist measurement to body height; cardiovas-
cular risk is lower if this ratio is less than 0.5. Experts consider drug
therapy to be justified in patients with increased risk factors and a
BMI ≥ 27 and in those without comorbidities but with a BMI ≥ 30.
Although the cause of obesity can be simply stated as energy
intake (dietary calories) that exceeds energy output (resting
metabolism plus exercise), the actual physiology of weight con-
trol is extremely complex, and the pathophysiology of obesity
is still poorly understood. Many hormones and neuronal mecha-
nisms regulate intake (appetite, satiety), processing (absorption,
conversion to fat, glycogen, etc), and output (thermogenesis,
muscle work). The fact that a large number of hormones reduce
appetite might appear to offer many targets for weight-reducing
drug therapy, but despite intensive research, no available phar-
macologic therapy has succeeded in maintaining a weight loss
of over 10% for 1 year. Furthermore, the social and psychological
aspects of eating are powerful influences that are independent
of or only partially dependent on the physiologic control mecha-
nisms. In contrast, bariatric (weight-reducing) surgery readily
achieves a sustained weight loss of 10–40%. Furthermore, surgery
effective nonbenzodiazepine anxiolytic (see Chapter 22). Appe-
tite suppression appears to be associated with agonist action at
5-HT2C receptors in the central nervous system, and dexfenflu-
ramine, a selective 5-HT agonist, was widely used as an appetite
suppressant but was withdrawn because of cardiac valvulopathy.
Lorcaserin, a 5-HT2C agonist, is approved by the FDA for use as
a weight-loss medication (see Box: Treatment of Obesity).
5-HT1D/1B Agonists & Migraine Headache
The 5-HT1D/1B agonists (triptans, eg, sumatriptan) are used almost
exclusively for migraine headache. Migraine in its “classic” form is
CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    289
that bypasses the stomach and upper small intestine (but not
simple restrictive banding) rapidly reverses some aspects of the
metabolic syndrome even before significant loss of weight. Even a
5–10% loss of weight is associated with a reduction in blood pres-
sure and improved glycemic control. Gastrointestinal flora also
influence metabolic efficiency, and research in mice suggests that
altering the microbiome can lead to weight gain or loss.
Until approximately 15 years ago, the most popular and
successful appetite suppressants were the nonselective 5-HT2
agonists fenfluramine and dexfenfluramine. Combined with
phentermine as Fen-Phen and Dex-Phen, they were moderately
effective. However, these 5-HT2 agonists were found to cause pulmo-
nary hypertension and cardiac valve defects and were withdrawn.
Older drugs still available in the USA and some other countries
include phenylpropanolamine, benzphetamine, amphetamine,
methamphetamine, phentermine, diethylpropion, mazindol, and
phendimetrazine. These drugs are all amphetamine mimics
and are central nervous system appetite suppressants; they are
generally helpful only during the first few weeks of therapy. Their
toxicity is significant and includes hypertension (with a risk of
cerebral hemorrhage) and addiction liability.
Liraglutide, lorcaserin, orlistat, and phentermine are the
only single-agent drugs currently approved in the USA for the treat-
ment of obesity. In addition, combination agents (phentermine
plus topiramate and naltrexone plus bupropion) are available.
These drugs have been intensely studied, and some of their prop-
erties are listed in Table 16–5. Clinical trials and phase 4 reports
suggest that these agents are modestly effective for the duration of
therapy (up to 1 year) and are probably safer than the single-agent
amphetamine mimics. However, they do not produce more than
a 5–10% loss of weight. Mirabegron, a β3 adrenoceptor agonist
approved for the treatment for overactive bladder (see Chapter 9),
is of possible future interest because β3 agonists activate brown
fat to consume more energy. Sibutramine and rimonabant were
marketed for several years but were withdrawn because of increas-
ing evidence of cardiovascular and other toxicities.
Because of the low efficacy and the toxicity of the available
drugs, intensive research continues. Because of the redundancy
of the physiologic mechanisms for control of body weight, it
seems likely that polypharmacy targeting multiple pathways will
be needed to achieve success.
characterized by an aura of variable duration that may involve nausea,
vomiting, visual scotomas or even hemianopsia, and speech abnor-
malities; the aura is followed by a severe throbbing unilateral headache
that lasts for a few hours to 1–2 days. “Common” migraine lacks the
aura phase, but the headache is similar. After more than a century of
intense study, the pathophysiology of migraine is still poorly under-
stood. Although the symptom pattern and duration of prodrome
and headache vary markedly among patients, the severity of migraine
headache justifies vigorous therapy in the great majority of cases.
Migraine involves the trigeminal nerve distribution to intra-
cranial (and possibly extracranial) arteries. These nerves release
290    SECTION IV  Drugs with Important Actions on Smooth Muscle

TABLE 16–5  Antiobesity drugs and their effects.

Drug or Drug Possible Mechanism
Combination Drug Group of Action Dosage Toxicity

Orlistat GI lipase inhibitor Reduces lipid absorption 60–120 mg TID PO Decreased absorption of fat-soluble
vitamins, flatulence, fecal incontinence
Liraglutide GLP-1 agonist Decreases appetite 3 mg/d SC Nausea, vomiting, pancreatitis
Lorcaserin 5-HT2c agonist Decreases appetite 10 mg PO BID Headache, nausea, dry mouth, dizziness,
constipation
Naltrexone/ Opioid antagonist Unknown 32 mg/ Headache, nausea, dizziness, constipation
bupropion + antidepressant 360 mg PO TID
Phentermine Sympathomimetic Norepinephrine release in CNS 30–37.5 mg/d PO Increased BP, HR; arrhythmias, insomnia, anxiety
Phentermine/ Sympathomimetic Norepinephrine release plus 3.75–15 mg/ Insomnia, dizziness, nausea, paresthesia,
topiramate + antiseizure agent unknown mechanism 23–92 mg PO dysgeusia
BID, twice daily; BP, blood pressure; CNS, central nervous system; GI, gastrointestinal; HR, heart rate; PO, by mouth; SC, subcutaneously; TID, three times daily.

peptide neurotransmitters, especially calcitonin gene-related structure to that of the 5-HT nucleus can be seen in the structure
peptide (CGRP; see Chapter 17), an extremely powerful vaso- below. These receptor types are found in cerebral and meningeal
dilator. Substance P and neurokinin A may also be involved. vessels and mediate vasoconstriction. They are also found on neu-
Extravasation of plasma and plasma proteins into the perivascular rons and probably function as presynaptic inhibitory receptors.
space appears to be a common feature of animal migraine models
and is found in biopsy specimens from migraine patients. This CH3
CH2 CH2 N
effect probably reflects the action of the neuropeptides on the CH3
CH3 NH SO2 CH2
vessels. The mechanical stretching caused by this perivascular
edema may be the immediate cause of activation of pain nerve N
endings in the dura. The onset of headache is sometimes associated
with a marked increase in amplitude of temporal artery pulsations, Sumatriptan
and relief of pain by administration of effective therapy is some-
times accompanied by diminution of these pulsations. In population studies, all of the triptan 5-HT1 agonists
The mechanisms of action of drugs used in migraine are poorly are as effective or more effective in migraine than other acute
understood, in part because they include such a wide variety of drug treatments, eg, parenteral, oral, and rectal ergot alkaloids.
drug groups and actions. In addition to the triptans, these include However, individual drugs in this class may have different
ergot alkaloids, nonsteroidal anti-inflammatory analgesic agents,
β-adrenoceptor blockers, calcium channel blockers, tricyclic
antidepressants and SSRIs, and several antiseizure agents. Further-
100
more, some of these drug groups are effective only for prophylaxis
and not for the acute attack. Persistent Persistent Photophobia
pain nausea
Two primary hypotheses have been proposed to explain the 80
actions of these drugs. First, the triptans, the ergot alkaloids, and
Percent of patients

antidepressants may activate 5-HT1D/1B receptors on presynaptic 60

trigeminal nerve endings to inhibit the release of vasodilating
peptides, and antiseizure agents may suppress excessive firing of
these nerve endings. Second, the vasoconstrictor actions of direct 40
5-HT agonists (the triptans and ergot) may prevent vasodilation
and stretching of the pain endings. It is possible that both mecha- 20
nisms contribute in the case of some drugs.
Sumatriptan and its congeners are currently first-line therapy
0
for acute severe migraine attacks in most patients (Figure 16–3). P S P S P S
However, they should not be used in patients at risk for coronary Treatment (P = placebo, S = sumatriptan)
artery disease. Anti-inflammatory analgesics such as aspirin and
ibuprofen are often helpful in controlling the pain of migraine. FIGURE 16–3  Effects of sumatriptan (734 patients) or placebo
Rarely, parenteral opioids may be needed in refractory cases. (370 patients) on symptoms of acute migraine headache 60 minutes
For patients with very severe nausea and vomiting, parenteral after injection of 6 mg subcutaneously. All differences between
metoclopramide may be helpful. placebo and sumatriptan were statistically significant. (Data from
Sumatriptan and the other triptans are selective agonists Cady RK et al: Treatment of acute migraine with subcutaneous sumatriptan. JAMA
for 5-HT1D and 5-HT1B receptors; the similarity of the triptan 1991;265:2831.)

TABLE 16–6  Pharmacokinetics of triptans.
Drug Routes Time to Onset (h)
Almotriptan Oral 2.6
Eletriptan Oral 2 20–40
Frovatriptan Oral 3 2.5
Naratriptan Oral 2 1–2.5
Rizatriptan Oral 1–2.5
Sumatriptan Oral, nasal, subcutaneous, 1.5 (0.2 for
rectal subcutaneous)
Zolmitriptan Oral, nasal 1.5–3
efficacies in individual patients. The pharmacokinetics and potencies
of the triptans differ significantly and are set forth in Table 16–6.
Most adverse effects are mild and include altered sensations
(tingling, warmth, etc), dizziness, muscle weakness, neck pain,
and for parenteral sumatriptan, injection site reactions. Chest
discomfort occurs in 1–5% of patients, and chest pain has been
reported, probably because of the ability of these drugs to cause
coronary vasospasm. They are therefore contraindicated in patients
with coronary artery disease and in patients with angina. Another
disadvantage is the fact that their duration of effect (especially
that of almotriptan, sumatriptan, rizatriptan, and zolmitriptan,
Table 16–6) is often shorter than the duration of the headache.
As a result, several doses may be required during a prolonged
migraine attack, but their adverse effects limit the maximum safe
daily dosage. Naratriptan and eletriptan are contraindicated in
patients with severe hepatic or renal impairment or peripheral vas-
cular syndromes; frovatriptan in patients with peripheral vascular
disease; and zolmitriptan in patients with Wolff-Parkinson-White
syndrome. The brand name triptans are extremely expensive; thus
generic sumatriptan should be used whenever possible.
Propranolol, amitriptyline, and some calcium channel block-
ers have been found to be effective for the prophylaxis of migraine
in some patients. They are of no value in the treatment of acute
migraine. The anticonvulsants valproic acid and topiramate (see
Chapter 24) have also been found to have some prophylactic effi-
cacy in migraine. Flunarizine, a calcium channel blocker used in
Europe, has been reported in clinical trials to effectively reduce the
severity of the acute attack and to prevent recurrences. Verapamil
appears to have modest efficacy as prophylaxis against migraine.
Other Serotonin Agonists in Clinical Use
Flibanserin, a 5-HT1a agonist and 5-HT2A antagonist, is approved
for treatment of hypoactive sexual desire disorder in women. Due
to inadequate evidence of efficacy, it was refused approval in
2010 and 2013. The clinical trials that led to its approval in 2015
showed a very small but significant increase in satisfactory sexual
desire and activities over several weeks of daily oral administra-
tion. Consumption of alcohol is contraindicated due to increased
risk of severe hypotension. Other adverse effects include syncope,
nausea, fatigue, dizziness, and somnolence.
CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    291
Maximum Dose
Single Dose (mg) per Day (mg) Half-Life (h)
6.25–12.5 25 3.3
80 4
7.5 27
5 5.5
5–10 30 2
25–100 (PO), 20 nasal, 200 2
6 subcutaneous, 25 rectal
2.5–5 10 2.8
Cisapride, a 5-HT4 agonist, was used in the treatment of
gastroesophageal reflux and motility disorders. Because of toxicity,
it is now available only for compassionate use in the USA. Tegas-
erod, a 5-HT4 partial agonist, is used for irritable bowel syndrome
with constipation (see Chapter 62).
Compounds such as fluoxetine and other SSRIs, which
modulate serotonergic transmission by blocking reuptake of the
transmitter, are among the most widely prescribed drugs for the
management of depression and similar disorders. These drugs are
discussed in Chapter 30.
SEROTONIN ANTAGONISTS
The actions of serotonin, like those of histamine, can be antago-
nized in several ways. Such antagonism is clearly desirable in those
rare patients who have carcinoid tumor and may also be valuable
in certain other conditions.
Serotonin synthesis can be inhibited by p-chlorophenylalanine
and p-chloroamphetamine. However, these agents are too toxic
for general use. Storage of serotonin can be inhibited by the use of
reserpine, but the sympatholytic effects of this drug (see Chapter 11)
and the high levels of circulating serotonin that result from release
prevent its use in carcinoid. Therefore, receptor blockade is the
major therapeutic approach to conditions of serotonin excess.
SEROTONIN-RECEPTOR
ANTAGONISTS
A wide variety of drugs with actions at other receptors (eg,
α adrenoceptors, H1-histamine receptors) also have serotonin
receptor-blocking effects. Phenoxybenzamine (see Chapter 10)
has a long-lasting blocking action at 5-HT2 receptors. In addition,
the ergot alkaloids discussed in the last portion of this chapter are
partial agonists at serotonin receptors.
Cyproheptadine resembles the phenothiazine antihistaminic
agents in chemical structure and has potent H1-receptor-blocking
as well as 5-HT2-blocking actions. The actions of cyproheptadine
are predictable from its H1 histamine and 5-HT receptor affini-
ties. It prevents the smooth muscle effects of both amines but has
292    SECTION IV  Drugs with Important Actions on Smooth Muscle
no effect on the gastric secretion stimulated by histamine. It also
has significant antimuscarinic effects and causes sedation.
The major clinical applications of cyproheptadine are in the
treatment of the smooth muscle manifestations of carcinoid
tumor and in cold-induced urticaria. The usual dosage in adults
is 12–16 mg/d orally in three or four divided doses. It is of some
value in serotonin syndrome, but because it is available only in
tablet form, cyproheptadine must be crushed and administered by
stomach tube in unconscious patients. The drug also appears to
reduce muscle spasms following spinal cord injury, in which con-
stitutive activity of 5-HT2C receptors is associated with increases
in Ca2+ currents leading to spasms. Anecdotal evidence suggests
some efficacy as an appetite stimulant in cancer patients, but
controlled trials have yielded mixed results.
Ketanserin blocks 5-HT2 receptors on smooth muscle and
other tissues and has little or no reported antagonist activity at
other 5-HT or H1 receptors. However, this drug potently blocks
vascular α1 adrenoceptors. The drug blocks 5-HT2 receptors on
platelets and antagonizes platelet aggregation promoted by
serotonin. The mechanism involved in ketanserin’s hypotensive
action probably involves α1 adrenoceptor blockade more than
5-HT2 receptor blockade. Ketanserin is available in Europe for
the treatment of hypertension and vasospastic conditions but
has not been approved in the USA. Ritanserin, another 5-HT2
antagonist, has little or no α-blocking action. It has been reported
to alter bleeding time and to reduce thromboxane formation,
presumably by altering platelet function.
Ondansetron is the prototypical 5-HT3 antagonist. This drug
and its analogs are very important in the prevention of nausea and
vomiting associated with surgery and cancer chemotherapy. They
are discussed in Chapter 62.
Considering the diverse effects attributed to serotonin and the
heterogeneous nature of 5-HT receptors, other selective 5-HT
antagonists may prove to be clinically useful.
■■ THE ERGOT ALKALOIDS
Ergot alkaloids are produced by Claviceps purpurea, a fungus that
infects grasses and grains—especially rye—under damp growing
or storage conditions. This fungus synthesizes histamine,
Ergot Poisoning: Not Just an Ancient Disease
As noted in the text, epidemics of ergotism, or poisoning by
ergot-contaminated grain, are known to have occurred sporadi-
cally in ancient times and through the Middle Ages. It is easy to
imagine the social chaos that might result if fiery pain, gangrene,
hallucinations, convulsions, and abortions occurred simultane-
ously throughout a community in which all or most of the people
believed in witchcraft, demonic possession, and the visitation
of supernatural punishments upon humans for their misdeeds.
Fortunately, such beliefs are uncommon today. However, ergot-
ism has not disappeared. A most convincing demonstration of
acetylcholine, tyramine, and other biologically active products in
addition to a score or more of unique ergot alkaloids. These alka-
loids affect α adrenoceptors, dopamine receptors, 5-HT receptors,
and perhaps other receptor types. Similar alkaloids are produced
by fungi parasitic to a number of other grass-like plants.
The accidental ingestion of ergot alkaloids in contaminated
grain can be traced back more than 2000 years from descriptions
of epidemics of ergot poisoning (ergotism). The most dramatic
effects of poisoning are dementia with florid hallucinations;
prolonged vasospasm, which may result in gangrene; and stimu-
lation of uterine smooth muscle, which in pregnancy may result
in abortion. In medieval times, ergot poisoning was called
St. Anthony’s fire after the saint whose help was sought in
relieving the burning pain of vasospastic ischemia. Identifiable
epidemics have occurred sporadically up to modern times (see
Box: Ergot Poisoning: Not Just an Ancient Disease) and mandate
continuous surveillance of all grains used for food. Poisoning of
grazing animals is common in many areas because the fungus
may grow on pasture grasses.
In addition to the effects noted above, the ergot alkaloids
produce a variety of other central nervous system and peripheral
effects. Detailed structure-activity analysis and appropriate semi-
synthetic modifications have yielded a large number of agents of
experimental and clinical interest.
BASIC PHARMACOLOGY OF ERGOT
ALKALOIDS
Chemistry & Pharmacokinetics
Two major families of compounds that incorporate the tetracyclic
ergoline nucleus may be identified; the amine alkaloids and the
peptide alkaloids (Table 16–7). Drugs of therapeutic and toxico-
logic importance are found in both groups.
The ergot alkaloids are variably absorbed from the gastro-
intestinal tract. The oral dose of ergotamine is about 10 times
larger than the intramuscular dose, but the speed of absorption
and peak blood levels after oral administration can be improved
by administration with caffeine (see below). The amine alkaloids
are also absorbed from the rectum and the buccal cavity and after
ergotism occurred in the small French village of Pont-Saint-Esprit
in 1951. It was vividly described in the British Medical Journal in
1951 (Gabbai et al, 1951) and in a later book-length narrative
account (Fuller, 1968). Several hundred individuals suffered symp-
toms of hallucinations, convulsions, and ischemia—and several
died—after eating bread made from contaminated flour. Similar
events have occurred even more recently when poverty, famine,
or incompetence resulted in the consumption of contaminated
grain. Ergot toxicity caused by excessive self-medication with
pharmaceutical ergot preparations is still occasionally reported.
 CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    293

TABLE 16–7  Major ergoline derivatives (ergot alkaloids).

Amine alkaloids Peptide alkaloids

H R8

8 O O
9 7 R2′
D N
6 H C NH 2′
5 N
12 10 CH3 N 5′
13 11
A C 9 O O
14 16 4 H R 5′
15 N
B 3 10 CH3
1 2
R1 N

1 2
HN R2

R1 R8 R2 R 2′ R 5′
6-Methylergoline H H
Ergotamine1 H CH3 CH2
Lysergic acid H COOH

Lysergic acid H O
diethylamide α-Ergocryptine H CH(CH3)2 CH2 CH(CH3)2
(LSD) C N(CH2 CH3)2

Ergonovine H O CH2OH Bromocriptine Br CH(CH3)2 CH2 CH(CH3)2

(ergometrine)
C NHCHCH3

1
Dihydroergotamine lacks the double bond between carbons 9 and 10.

administration by aerosol inhaler. Absorption after intramuscular
injection is slow but usually reliable. Semisynthetic analogs such
as bromocriptine and cabergoline are well absorbed from the
gastrointestinal tract.
The ergot alkaloids are extensively metabolized in the body.
The primary metabolites are hydroxylated in the A ring, and
peptide alkaloids are also modified in the peptide moiety.
Pharmacodynamics
A. Mechanism of Action
The ergot alkaloids act on several types of receptors. As
shown by the color outlines in Table 16–7, the nuclei of both
catecholamines (phenylethylamine, left panel) and 5-HT (indole-
thylamine, right panel) can be discerned in the ergoline nucleus.
Their effects include agonist, partial agonist, and antagonist
actions at α adrenoceptors and serotonin receptors (especially
5-HT1A and 5-HT1D; less for 5-HT2 and 5-HT3); and agonist
or partial agonist actions at central nervous system dopamine
receptors (Table 16–8). Furthermore, some members of the ergot
family have a high affinity for presynaptic receptors, whereas
others are more selective for postjunctional receptors. There is
a powerful stimulant effect on the uterus that seems to be most
closely associated with agonist or partial agonist effects at 5-HT2
receptors. Structural variations increase the selectivity of certain
members of the family for specific receptor types.

TABLE 16–8  Effects of ergot alkaloids at several receptors.1

Serotonin Receptor Uterine Smooth
Ergot Alkaloid α Adrenoceptor Dopamine Receptor (5-HT2) Muscle Stimulation

Bromocriptine − +++ − 0
Ergonovine ++ − (PA) +++ ++
Ergotamine − − (PA) 0 +(PA) +++
Lysergic acid diethylamide (LSD) 0 +++ − − (++ in CNS) +
Methysergide +/0 +/0 − − − (PA) +/0
1
Agonist effects are indicated by +, antagonist by −, no effect by 0. Relative affinity for the receptor is indicated by the number of + or − signs. PA means partial agonist
(both agonist and antagonist effects can be detected).
294    SECTION IV  Drugs with Important Actions on Smooth Muscle
B. Organ System Effects
1. Central nervous system—As indicated by traditional
descriptions of ergotism, certain of the naturally occurring alka-
loids are powerful hallucinogens. Lysergic acid diethylamide
(LSD; “acid”) is a synthetic ergot compound that clearly dem-
onstrates this action. The drug has been used in the laboratory
as a potent peripheral 5-HT2 antagonist, but good evidence sug-
gests that its behavioral effects are mediated by agonist effects at
prejunctional or postjunctional 5-HT2 receptors in the central
nervous system. In spite of extensive research, no clinical value has
been discovered for LSD’s dramatic central nervous system effects.
Abuse of this drug has waxed and waned but is still widespread. It
is discussed in Chapter 32.
Dopamine receptors in the central nervous system play
important roles in extrapyramidal motor control and the regu-
lation of pituitary prolactin release. The actions of the peptide
ergoline bromocriptine on the extrapyramidal system are dis-
cussed in Chapter 28. Of all the currently available ergot
derivatives, bromocriptine, cabergoline, and pergolide have the
highest selectivity for the pituitary dopamine receptors. These
drugs directly suppress prolactin secretion from pituitary cells
by activating regulatory dopamine receptors (see Chapter 37).
They compete for binding to these sites with dopamine itself and
with other dopamine agonists such as apomorphine. They bind
with high affinity and dissociate slowly.
2. Vascular smooth muscle—The actions of ergot alkaloids
on vascular smooth muscle are drug-, species-, and vessel-
dependent, so few generalizations are possible. In humans, ergota-
mine and similar compounds constrict most vessels in nanomolar
concentrations (Figure 16–4). The vasospasm is prolonged. This
response is partially blocked by conventional α-blocking agents.
However, ergotamine’s effect is also associated with “epinephrine
reversal” (see Chapter 10) and with blockade of the response to
other α agonists. This dual effect reflects the drug’s partial agonist
120
Percent of maximum 5-HT contraction
100
80
60
40
20
0
−10
FIGURE 16–4  Effects of ergot derivatives on contraction of isolated segments of human basilar artery strips removed at surgery. All of
the ergot derivatives are partial agonists; and all are more potent than the full agonists, norepinephrine and serotonin. DHE, dihydroergota-
mine; ERG, ergotamine; 5-HT, serotonin; MS, methysergide; MT, methylergometrine; NE, norepinephrine. (Reproduced, with permission, from Müller-
Schweinitzer E. In: 5-Hydroxytryptamine Mechanisms in Primary Headaches. Olesen J, Saxena PR [editors]. Raven Press, 1992.)
action (Table 16–7). Because ergotamine dissociates very slowly
from the α receptor, it produces very long-lasting agonist and
antagonist effects at this receptor. There is little or no effect at β
adrenoceptors.
Although much of the vasoconstriction elicited by ergot
alkaloids can be ascribed to partial agonist effects at α adreno-
ceptors, some may be the result of effects at 5-HT receptors.
Ergotamine, ergonovine, and methysergide all have partial agonist
effects at 5-HT2 vascular receptors. The remarkably selective
antimigraine action of the ergot derivatives was originally thought
to be related to their actions on vascular serotonin receptors. Cur-
rent hypotheses, however, emphasize their action on prejunctional
neuronal 5-HT receptors.
After overdosage with ergotamine and similar agents, vasospasm
is severe and prolonged (see Toxicity, below). This vasospasm is
not easily reversed by α antagonists, serotonin antagonists, or
combinations of both.
Ergotamine is typical of the ergot alkaloids that have a strong
vasoconstrictor action. The hydrogenation of ergot alkaloids at
the 9 and 10 positions (Table 16–6) yields dihydro derivatives
that have reduced serotonin partial agonist and vasoconstrictor
effects and increased selective α-receptor-blocking actions.
3. Uterine smooth muscle—The stimulant action of ergot
alkaloids on the uterus, as on vascular smooth muscle, appears
to combine α agonist, serotonin agonist, and other effects.
Furthermore, the sensitivity of the uterus to the stimulant
effects of ergot increases dramatically during pregnancy, perhaps
because of increasing dominance of α1 receptors of the uterus
as pregnancy progresses. As a result, the uterus at term is more
sensitive to ergot than earlier in pregnancy and far more sensi-
tive than the nonpregnant organ.
In very small doses, ergot preparations can evoke rhythmic
contraction and relaxation of the uterus. At higher concentra-
tions, these drugs induce powerful and prolonged contracture.
Ergonovine is more selective than other ergot alkaloids in affecting
NE
5-HT
ERG MT
DHE
MS
−9 −8 −7 −6 −5 −4
Concentration (log M)

the uterus and is an agent of choice in obstetric applications of the
ergot drugs although oxytocin, the peptide hormone, is preferred
in most cases.
4. Other smooth muscle organs—In most patients, the ergot
alkaloids have little or no effect on bronchiolar or urinary smooth
muscle. The gastrointestinal tract, on the other hand, is quite
sensitive. In some patients, nausea, vomiting, and diarrhea may be
induced even by low doses. The effect is consistent with action on
the central nervous system emetic center and on gastrointestinal
serotonin receptors.
CLINICAL PHARMACOLOGY OF
ERGOT ALKALOIDS
Clinical Uses
Despite their significant toxicities, ergot alkaloids are still widely
used in patients with migraine headache or pituitary dysfunction.
They are used only occasionally in the postpartum patient.
A. Migraine
Ergot derivatives are highly specific for migraine pain; they are
not analgesic for any other condition. Although the triptan drugs
discussed above are preferred by most clinicians and patients, tra-
ditional therapy with ergotamine can also be effective when given
during the prodrome of an attack; it becomes progressively less
effective if delayed. Ergotamine tartrate is available for oral, sub-
lingual, rectal suppository, and inhaler use. It is often combined
with caffeine (100 mg caffeine for each 1 mg ergotamine tartrate)
to facilitate absorption of the ergot alkaloid.
The vasoconstriction induced by ergotamine is long-lasting
and cumulative when the drug is taken repeatedly, as in a severe
migraine attack. Therefore, patients must be carefully informed
that no more than 6 mg of the oral preparation may be taken for
each attack and no more than 10 mg per week. For very severe
attacks, ergotamine tartrate, 0.25–0.5 mg, may be given intrave-
nously or intramuscularly. Dihydroergotamine, 0.5–1 mg intrave-
nously, is favored by some clinicians for treatment of intractable
migraine. Intranasal dihydroergotamine may also be effective.
Methysergide, which was used for migraine prophylaxis in the
past, was withdrawn because of toxicity, see below.
B. Hyperprolactinemia
Increased serum levels of the anterior pituitary hormone prolactin
are associated with secreting tumors of the gland and also with
the use of centrally acting dopamine antagonists, especially the
D2-blocking antipsychotic drugs. Because of negative feedback
effects, hyperprolactinemia is associated with amenorrhea and
infertility in women as well as galactorrhea in both sexes. Rarely,
the prolactin surge that occurs around the end-of-term pregnancy
may be associated with heart failure; cabergoline has been used to
treat this cardiac condition successfully.
Bromocriptine is extremely effective in reducing the high
levels of prolactin that result from pituitary tumors and has
CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    295
even been associated with regression of the tumor in some
cases. The usual dosage of bromocriptine is 2.5 mg two or
three times daily. Cabergoline is similar but more potent.
Bromocriptine has also been used in the same dosage to sup-
press physiologic lactation. However, serious postpartum car-
diovascular toxicity has been reported in association with the
latter use of bromocriptine or pergolide, and this application
is discouraged (see Chapter 37).
C. Postpartum Hemorrhage
The uterus at term is extremely sensitive to the stimulant action of
ergot, and even moderate doses produce a prolonged and powerful
spasm of the muscle quite unlike natural labor. Therefore, ergot
derivatives should be used only for control of postpartum uterine
bleeding and should never be given before delivery. Oxytocin is
the preferred agent for control of postpartum hemorrhage, but
if this peptide agent is ineffective, ergonovine maleate, 0.2 mg
given intramuscularly, can be tried. It is usually effective within
1–5 minutes and is less toxic than other ergot derivatives for this
application. It is given at the time of delivery of the placenta or
immediately afterward if bleeding is significant.
D. Diagnosis of Variant Angina
Ergonovine given intravenously has been used to produce
prompt vasoconstriction during coronary angiography to diag-
nose variant angina if reactive segments of the coronary arteries
are present. In Europe, methylergometrine has been used for
this purpose.
E. Senile Cerebral Insufficiency
Dihydroergotoxine, a mixture of dihydro-α-ergocryptine and
three similar dihydrogenated peptide ergot alkaloids (ergoloid
mesylates), has been promoted for many years for the relief
of signs of senility and, more recently, for the treatment of
Alzheimer’s dementia. There is no useful evidence that this drug
has significant benefit.
Toxicity & Contraindications
The most common toxic effects of the ergot derivatives are
gastrointestinal disturbances, including diarrhea, nausea, and
vomiting. Activation of the medullary vomiting center and of the
gastrointestinal serotonin receptors is involved. Since migraine
attacks are often associated with these symptoms before therapy
is begun, these adverse effects are rarely contraindications to the
use of ergot.
A more dangerous toxic effect—usually associated with
overdosage—of agents like ergotamine and ergonovine is
prolonged vasospasm. This sign of vascular smooth muscle
stimulation may result in gangrene and may require amputation.
Bowel infarction has also been reported and may require resection.
Vasospasm caused by ergot is refractory to most vasodilators, but
infusion of large doses of nitroprusside or nitroglycerin has been
successful in some cases.
Chronic therapy with methysergide was associated with con-
nective tissue proliferation in the retroperitoneal space, the pleural
296    SECTION IV  Drugs with Important Actions on Smooth Muscle

cavity, and the endocardial tissue of the heart. These changes
occurred insidiously over months and presented as hydronephro-
sis (from obstruction of the ureters) or a cardiac murmur (from
distortion of the valves of the heart). In some cases, valve damage
required surgical replacement. As a result, this drug was with-
drawn from the US market. Similar fibrotic change has resulted
from the chronic use of non-ergot 5-HT agonists promoted in the
past for weight loss (fenfluramine, dexfenfluramine).
Other toxic effects of the ergot alkaloids include drowsi-
ness and, in the case of methysergide, occasional instances of
central stimulation and hallucinations. In fact, methysergide
was sometimes used as a substitute for LSD by members of the
so-called drug culture.
Contraindications to the use of ergot derivatives consist of the
obstructive vascular diseases, especially symptomatic coronary
artery disease, and collagen diseases.
There is no evidence that ordinary use of ergotamine for
migraine is hazardous in pregnancy. However, most clinicians
counsel restraint in the use of the ergot derivatives by preg-
nant patients. Use to deliberately cause abortion is contrain-
dicated because the high doses required often cause dangerous
vasoconstriction.

SUMMARY Drugs with Actions on Histamine and Serotonin Receptors; Ergot

Alkaloids
Mechanism Clinical Pharmacokinetics, Toxicities,
Subclass, Drug of Action Effects Applications Interactions

H1 ANTIHISTAMINES
First generation:
  •  Diphenhydramine
Competitive Reduces or prevents histamine IgE immediate Oral and parenteral • duration 4–6 h • Toxicity:
antagonism/inverse effects on smooth muscle, allergies; especially Sedation when used in hay fever, muscarinic
agonism at H1 immune cells • also blocks hay fever, urticaria blockade symptoms, orthostatic hypotension
receptors muscarinic and α adrenoceptors • often used as a • Interactions: Additive sedation with other
• highly sedative sedative, antiemetic, sedatives, including alcohol • some inhibition of
and anti-motion CYP2D6, may prolong action of some β blockers
sickness drug

Second generation:
  •  Cetirizine Competitive Reduces or prevents histamine IgE immediate Oral • duration 12–24 h • Toxicity: Sedation and
antagonism/inverse effects on smooth muscle, allergies; especially arrhythmias in overdose • Interactions: Minimal
agonism at H1 immune cells hay fever, urticaria
receptors

  • Other first-generation H1 blockers: Chlorpheniramine is a less sedating H1 blocker with fewer autonomic effects. Doxylamine, a strongly sedating H1 blocker, is available
over-the-counter in many sleep-aid formulations and in Diclegis (in combination with pyridoxine) for use in nausea and vomiting of pregnancy
  •  Other second-generation H1 blockers: Loratadine, desloratadine, and fexofenadine are very similar to cetirizine

H2 ANTIHISTAMINES
  •  Cimetidine, others (see Chapter 62)

SEROTONIN AGONISTS
5-HT1B/1D:
  •  Sumatriptan Partial agonist at Effects not fully understood Migraine and cluster Oral, nasal, parenteral • duration 2 h • Toxicity:
5-HT1B/1D receptors • may reduce release of headache Paresthesias, dizziness, coronary
calcitonin gene-related peptide vasoconstriction • Interactions: Additive with
and perivascular edema in other vasoconstrictors
cerebral circulation

  • Other triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan): Similar to sumatriptan except for pharmacokinetics (2–6 h duration of action);
much more expensive than generic sumatriptan

5-HT2C:
  •  Lorcaserin Agonist at 5-HT2C Appears to reduce appetite Obesity Oral • duration 11 h • Toxicity: Dizziness,
receptors headache, constipation

5-HT4:
  •  Tegaserod (see Chapter 62)

(continued)
 CHAPTER 16  Histamine, Serotonin, & the Ergot Alkaloids    297

Mechanism Clinical Pharmacokinetics, Toxicities,

Subclass, Drug of Action Effects Applications Interactions

SEROTONIN BLOCKERS
5-HT2:
  • Ketanserin (not Competitive Prevents vasoconstriction and Hypertension Oral • duration 12–24 h • Toxicity: Hypotension
available in USA) blockade at 5-HT2 bronchospasm of carcinoid • carcinoid syndrome
receptors syndrome associated with
carcinoid tumor

5-HT3:
  •  Ondansetron, others (see Chapter 62)

ERGOT ALKALOIDS
Vasoselective:
  •  Ergotamine Mixed partial agonist Causes marked smooth muscle Migraine and cluster Oral, parenteral • duration 12–24 h • Toxicity:
effects at 5-HT2 and contraction but blocks headache Prolonged vasospasm causing angina,
α adrenoceptors α-agonist vasoconstriction gangrene; uterine spasm

Uteroselective:
  •  Ergonovine Mixed partial agonist Same as ergotamine • some Postpartum bleeding Oral, parenteral (methylergonovine) • duration
effects at 5-HT2 and selectivity for uterine smooth • migraine headache 2–4 h • Toxicity: Same as ergotamine
α adrenoceptors muscle

CNS selective:
  • Lysergic acid Central nervous Hallucinations None • widely Oral • duration several hours • Toxicity:
diethylamide system 5-HT2 and • psychotomimetic abused Prolonged psychotic state, flashbacks
dopamine agonist
• 5-HT2 antagonist in
periphery

  • Bromocriptine, pergolide: Ergot derivatives used in Parkinson’s disease (see Chapter 28) and prolactinoma (see Chapter 37). Pergolide used in equine
Cushing’s disease

P R E P A R A T I O N S A V A I L A B L E

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

ANTIHISTAMINES (H 1 BLOCKERS) * Fexofenadine Generic, Allegra
Azelastine Generic, Astelin (nasal), Optivar
Hydroxyzine Generic, Vistaril
(ophthalmic)
Ketotifen Generic, Zaditor
Brompheniramine Brovex, Dimetapp, others
Levocabastine Livostin
Buclizine Bucladin-S Softabs
Levocetirizine Generic, Xyzal
Carbinoxamine Generic, Histex
Loratadine Generic, Claritin
Cetirizine Generic, Zyrtec
Chlorpheniramine Generic, Chlor-Trimeton Meclizine Generic, Antivert, Bonine

Clemastine Generic, Tavist Olopatadine Patanol, Pataday

Cyclizine Generic, Marezine Phenindamine Nolahist

Cyproheptadine Generic, Periactin Promethazine Generic, Phenergan

Desloratadine Generic, Clarinex Triprolidine Generic, Zymine, Tripohist

Dimenhydrinate †
Generic, Dramamine H 2 BLOCKERS

Diphenhydramine Generic, Benadryl See Chapter 62.

Doxylamine Diclegis (combination with 5-HT AGONISTS

pyridoxine), Unisom Sleep Tabs Almotriptan Axert
Epinastine Generic, Elestat Eletriptan Relpax
(continued)
298    SECTION IV  Drugs with Important Actions on Smooth Muscle

GENERIC NAME AVAILABLE AS GENERIC NAME AVAILABLE AS

Flibanserin Addyi Ergonovine Generic, Ergotrate
Frovatriptan Frova Ergotamine mixtures Generic, Cafergot
Naratriptan Generic, Amerge (include caffeine)

Rizatriptan Generic, Maxalt, Maxalt-MLT Ergotamine tartra Generic, Ergomar

Sumatriptan Generic, Imitrex Methylergonovine Generic, Methergine

Zolmitriptan Generic, Zomig ANTIOBESITY DRUGS

5-HT ANTAGONISTS Liraglutide Saxenda, Victoza

See Chapter 62. Lorcaserin Belviq
MELATONIN RECEPTOR AGONISTS Naltrexone/bupropion Contrave
Ramelteon Rozarem Orlistat Alli, Xenical
Tasimelteon Hetlioz Phentermine Generic, Adipex-P,
ERGOT ALKALOIDS Lomaira
Dihydroergotamine Generic, Migranal, D.H.E. 45 Phentermine/topiramate Qsymia

*Several other antihistamines are available only in combination products with, for example, phenylephrine.
†
Dimenhydrinate is the chlorotheophylline salt of diphenhydramine.

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C ASE STUDY ANSWER
These patients demonstrate typical symptoms and signs
caused by histamine. Fortunately, neither patient in this
episode of food poisoning had significant laryngeal edema
or bronchospasm. Certain types of fish, if improperly
preserved, contain large quantities of histamine, due to
the conversion—by bacteria contaminating the muscle
tissue—of histidine to histamine. If consumed in suf-
ficient amount, enough histamine can be absorbed to
cause the clinical picture described. This syndrome is
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termed scombroid poisoning (Scombridae family of fish is
most commonly associated with this toxicity). Treatment
with maximal doses of histamine blockers, especially H1
blockers, is usually sufficient to control the symptoms.
Because this is not an allergic reaction, administration of
epinephrine is not necessary unless hypotension or airway
obstruction is severe. (See Edlow JA: The Deadly Dinner
Party: And Other Medical Detective Stories. Yale University
Press, 2009.)